pr©sentation powerpoint - universit© de sherbrooke
TRANSCRIPT
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RÉPONSE IMMUNE CHEZ LA PERSONNE
ÂGÉE
Tamas Fulop M.D., PhD
Centre de recherche sur le vieillissement,
Service de Gériatrie, Département de médecine
Faculté de Médecine, Université de Sherbrooke
Gérontoclub, 30 Mars 2012, Sherbrooke
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Divulgation de conflits d’intérêts potentiels
Merck: conférences
Pfizer: consultant
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PLAN
1. Concept de l’immunosenescence
2. Rôle dans les maladies associées au vieillissement
3. Déterminer le rôle de l’immunosenescence dans
la conceptualisation de la fragilité
4. Réponse et barrière à la vaccination
5. Perspectives
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The immune system
adaptive (memory) non-adaptive (innate)
B cells
(humoral via
antibodies)
T cells
(cellular effectors;
cytokines)
antigen-presenting
cells
dendritic
cells
phagocytes
NK cells
A.E. 1998
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Séquence d’activation du système immun inné et adaptative
lors d’une infection
Lord et al. MAD 2001
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www.goodpsych.com/stress-psychology/
Coopération entre la réponse immune innée et adaptative
?
?
?
?
?
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The adaptive immune response
APC
MHC
B-memory cell
B-cell
Plasma cell
antibodies
T-memory cell
T-cell
TCR
Cytokines
Cytotoxicity
Pathogen
T cell helper
function
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Activation
des
cellules T
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clonal expansion
IL2 gene
IL2 receptor gene
IL2-secretion
IL2-receptor
autocrine proliferation
Costimulation
TCR Ag/MHC
complex
T cell activation
Requirements for T cell-mediated
immune response
CD28
eg. virus
....and
exhaustion
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Th1
Th2
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Immunosenescence
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Changements physiologiques principaux avec l’âge
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Pathologies infectieuses du sujet âgé
• L’incidence des infections augmente avec l ’âge
• Le risque d’infections nosocomiales est multiplié par 3 à 5 chez
le sujet âgé par rapport à l ’adulte d ’âge moyen
• La gravité des infections augmente avec:
- L ’âge
- Le terrain fragilisé par la polypathologie
- Et/ou la perte d ’autonomie
- Diagnostic tardif et moins agressif
• La mortalité d’origine infectieuse augmente avec l’âge
• L’évolution vers la guérison plus lente
Groupe de travail sur la vaccination en gériatrie
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Pourquoi?
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CAUSES DE L’AUGMENTATION DE LA
SUSCEPTIBILITÉ DES PERSONNES ÂGÉES AUX
INFECTIONS
1. Dérégulation de la réponse immune - innée
- adaptative
2. Malnutrition
2. Maladies chroniques et degeneratives: diabète
insuffisance cardio-respiratoire
fragilité
4. Médications et iatrogenie
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IMMUNITÉ ET VIEILLISSEMENT
•VIEILLISSEMENT: Dérégulation immune
•CAUSE: multifactorielle
-génétique
-environnemental: nutrition
•ALTERATION FONDAMENTALE: immunité cellulaire
•MODULABLE
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Decreased Increased CD3+ cells (slightly) CD3+DR+ cells TCR1 ( ) cells (slightly) TCR oligoclonality CD4+CD7+ cells TCR variants (mutants) CD4+ cells (slightly or unchanged) CD4+CD8 ( )+ cells CD45RA+ cells CD45RO+ cells CD28+ cells CD28-negative cells CD95+ cells CD152 (CTLA-4)+ cells
........many changes have been reported over the years but
there is little agreement between studies
Quels changements dans les cellules T font
consensus par la majorité des investigateurs?
Why is there so little agreement in the literature? Pawelec. G et al
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Proliferation with mitogens TCR signal transduction Nuclear transcription factor activation
(AP-1, NF-AT, NF- B)
IL 2 secretion IL 10 secretion soluble IL 2R secretion IL 6 secretion
IL 2R expression after activation TNF- secretion CTL generation CD40L (CD154) upregulation and thus B cell help
Telomere lengths DNA damage
Telomerase induction DNA repair hprt & HLA mutations;
Consensus?
Fonctions
Decreased Increased
Why is there so little agreement in the literature? Pawelec. G et al
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One possible solution: selection of “successfully aged”
Age-associated changes:
Commonly seen in centenarians Not often seen in centenarians
Ig organ-specific Ab
non-organ-specific Ab NK activity
IL 6 TNF-
T cell proliferation
oxidative stress resistance
(therefore less relevant (therefore more relevant to healthy ageing?) to healthy ageing?)
Pawelec. G et al
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Quels paramètres sont importants pour
le vieillissement à succès?
Jönköping OCTO/NONA longitudinal studies are
determining an „immunological risk phenotype“
predicting mortality in the very old
The IRP is characterised by
CD4:8 ratio of < 1
poor T cell proliferative responses
increased CD8-positive CD28-negative cells
low B cells
CMV-seropositivity
Wikby 2000, Olsson 2001, Pawelec 2001, Nilsson 2002
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IMMUNITÉ CELLULAIRE: Lymphocytes T
CAUSES INTRINSÈQUES DES ALTÉRATIONS
Stimulation antigénique chronique
Involution thymique
Altération dans la transduction des signaux intracellulaires
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It is suggested that many of these changes are caused by:
chronic antigenic stress and oxidative stress
stimulation by tumour antigens in cancer patients
stimulation by persistent viruses in the elderly. • CMV, Herpes
• Varicella-Zoster Virus (VZV)
The CD8 cells are characterised by increased resistance to
apoptosis and the CD4 cells by increased susceptibility
Hence dysfunctional CD8 cells accumulate and specific CD4
cells are clonally deleted;
the CD4:8 ratio can become inverted
Chronic antigenic stress
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CD57 expression on CD8+ T-cells
Seropositive Seronegative0
10
20
30
40
50
60
70
% p
osi
tive
cel
ls
CD57+KLRG1+ CD8+T-cells
Seropositive Seronegative0
5
10
15
20
25
30
35
40
45
50
55
KLRG1+ CD8+T-cells
Seropositive Seronegative05
101520253035404550556065
CMV infection is associated with accumulation of the
most late-differentiated CD8 cells
Derhovanessian 2008
Most age-associated changes
are exacerbated by or even
caused by, chronic antigenic
stressors, commonly CMV
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25
High et al .JAGS. 2010
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Activation of
naive cells
Expansion
(ca. 28 PD
in IM)
Contraction Memory
Apoptosis Cytokines (IL-15)
Antigen
Compromised
in the elderly
Resultat: accumulation de cellules dysfunctionnelles
Dysfunctional cells
Conclusion: In IRP elderly, dysfunctional CD8+ CMV-specific T cells
accumulate because apoptotic pathways are compromised.
Hypothesis: Because T cell homeostasis maintains constant numbers
of T cells in the periphery, even if naive cells continue to be generated
from the thymus, the T cell repertoire will be shrunken, contributing to
increased susceptibility to infectious disease
Pawelec. G et al
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Involution of the thymus
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Gads
Ras
Sos
Raf-1
MEK
ERK1/2
MEKK-1
MKK
JNK p38
PKC
MAPKKK
IkB
NF-kB
IKK
ζ-chains
Ca2+
Grb2
Calcineurin
Calmodulin
IP3-R
SLP-76
Vav Nck
Fyb
SKAP55
Cdc42 Rac
WASP
PAK1
CD45
IL-2
Cytoskeleton
PIP2
IP3 +
DAG
Jun
Elk-1
Telomerase
NF-AT Fos ATF-2
ZAP-70 PLC-γ1
Bad
Bcl-2
Bcl-Xl
CD95
CD95L
PKB/Akt
nucleus
ER
Lipid rafts
Ca2+
Lck
T-Cell Receptor LAT CD4/CD8
membrane
PI3K
CD28
Altered raft
recruitment? Altered lipid/protein
composition?
Fulop et al. Drugs and Aging 2005
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CD4 CD8
Young Elderly
CD4 CD8
pLck NS
S pLck
CD4 CD8
Young Elderly
CD4 CD8
pLAT
pLAT
NS
S
Phosphorylation of Lck and LAT in rafts of CD4+ & CD8+
Lck LAT
Y
E
CD4+ CD8+ CD4+ CD8+
*
*
Y
E
* *
Larbi et al. Cell Signal. 2006
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Lck regulatory
loop in T cells
of young and
elderly subjects
after CD3/CD28
stimulation
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Analysis by confocal microscopy of the
coalescence of lipid rafts
0 32
2 µm
Poly-L-lysine anti-CD3 anti-CD3/anti-28
coated coverslip coated coverslip coated coverslip
Young
Elderly
Larbi et al. J. Leuk. Biol. 2004
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RESULTS ON T CELL SUB-POPULATIONS
MARQUED CHANGES WITH AGING
IN THE MEMBRANE COMPOSITION
AND FUNCTION OF CD4+
CD4 CD8
Young
Aged
Resting cells
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CHOLESTEROL REGULATION
AT THE CELLULAR LEVEL
Esterification
Biosynthesis
Hydrolysis
Efflux
Influx
CE
ER
TGN
GOLGI
« The modification of one of these process could lead to a variety of pathology » K.Simons et al, 2002, J. Clin. Invest.
LDL-R
(SRB-1)
HMGCoA
Réductase
ACAT
ABCA1
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Cholesterol concentration is more important in all fractions BUT ONLY
significant in lipid rafts
Cholesterol measurement (nM) in fractions
Elderly Young Ratio E/Y
1 58 + 6 28 + 3 2.1
2 80 + 4 29 + 1 2.8
3 69 + 6 30 + 5 2.3
4 62 + 6 36 + 4 1.7
5 68 + 2 32 + 6 2.1
6 68 + 3 37 + 6 1.9
7 62 + 1 40 + 3 1.6
8 69 + 1 53 + 6 1.3
9 68 + 8 46 + 6 1.5
Lipid rafts
* *
*
* p < 0.05
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INNATE IMMUNITY
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Schröder and Rink MAD 2003
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Reduced neutrophil response towards chemoattractant
with aging
Fulop et al. Ageing Cell. 2004
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Production of superoxide anion by neutrophils with aging
under FMLP stimulation and after GM-CSF priming
Fulop et al. Ageing Cell. 2004
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Activation of Jak2 in PMN from young and elderly subjects
exposed to GM-CSF
Fortin et al. Biogerontology, 2007
Phosphorylation of JAK2 with GM-CSF, inhibited by AG490 in young.
Effect of GM-CSF still present at 18h.
GM-CSF inhibited JAK2 phosphorylation on PMN of elderly.
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Gomez RC et al. MAD, 43, 2008
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Derhovanessian et al.Immum. Age. 2008
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45 45 High et al .JAGS. 2010
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Proliferation
Cytokine +++
CD94/NKG2Ahigh
KIR-
Perforin +/-
Longer telomeres
AGE
Proliferation
Cytokine +++
CD94/NKG2Ahigh
KIR-
Perforin +/-
Longer telomeres
CD56bright
Natural Cytotoxicity
ADCC
CD16+
KIR+
CD94+
Shorter telomeres
CD56dimCD57neg
Natural Cytotoxicity
ADCC
CD16++
KIR++
CD94+/-
CD56dimCD57+
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Neutrophils in the aged
Preserved
• Number
• Adherence
• TLR expression
Reduced
• Chemotaxis
• Phagocytosis
• SuperOxide production
• Molecules recruitment into lipid raft
• Signal transduction
• Apoptosis
Macrophages in the aged
Preserved • Number (altered subsets)
Reduced • Chemotaxis
• Apoptosis
• Phagocytosis
• SuperOxide production
• TLR expression and function
• MHC class II expression
• Signal transduction
• Cytokine production
Increased • PGE2 production
Dendritic cells in the aged pDC:
• Decreased IFN-I/III production
• Decreased antigen presentation
mDC:
• Decreased TLR-mediated signalling
• Decreased antigen presentation
• Decreased chemoraxis and endocytosis
Neutrophils
Dendritic cells
Macrophages
Pathogens
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Élimination du pathogène
Inflammation controllée
Homéostasie cellulaire
Mémoire immunitaire
V
I
E
IL
LI
S
S
E
M
E
N
T
Déclin des fonctions immunitaires: surtout chez les lymphocytes T
V
I
E
I
L
L
I
S
S
E
M
E
N
T
V
I
E
I
L
L
I
S
S
E
M
E
N
T
Le système immunitaire et le vieillissement
C’est l’IMMUNOSÉNESCENCE
Le vieillissement humain s’accompagne d’une plus grande susceptibilité
aux infections, maladies autoimmunes, maladies d’Alzheimer et cancers.
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Sujet âgé sain
monocyte
macrophage lymphocyte
20% CD3 et CD4
60% capacités
prolifératives
Stimulation
immunitaire
IL 1
IL 6
TNF
déficit fonctionnel
fonctionnels
Réponse inadaptée
Syndrome inflammatoire prolongé
Groupe de travail sur la vaccination en gériatrie
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Le syndrome inflammatoire chez les sujets âgés
• Syndrome inflammatoire chronique : situation fréquente en gériatrie
• En cas d ’infection, le syndrome inflammatoire est plus intense et plus prolongé chez les sujets âgés
• Le syndrome inflammatoire => activation des macrophages et forte production de cytokines pro-inflammatoires (IL-1, IL-6, Tumor Necrosis Factor)
• Dérégulation hormonale: Neurohormone, Leptine
Anorexie
hypercatabolisme
CONSEQUENCES
Fonte musculaire, aggravation de la dénutrition, réduction des possibilités de récupération
Groupe de travail sur la vaccination en gériatrie
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Caractéristiques de l’inflamm-aging
1. À bas bruit
2. Contrôlée
3. Asymptomatique
4. Chronique
5. Inflammation systémique
6. cytokines pro-inflammatoires (IL-6, IL-15), infection CMV,
ROS)
dommages tissulaires discrets continus
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Les maladies potentiellement associées à la
dérégulation de la fonction des cellules immunes avec
l’âge
Infections: bactériennes et virales
Cancers
Dérégulation et maladies autoimmunees
Maladies inflammatoires chroniques: maladies cardio-vasculaires
maladie d’Alzheimer
C
L
A
S
S
I
Q
U
E
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Maladie d’Alzheimer
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Le plus grand facteur de risque est l’âge
Est une maladie systémique
Tout le système immun est mis à contribution
Production des ROS est augmentée
Les facteurs vasculaires jouent un rôle
ApoE4 et TLR4 sont des gènes de susceptibilité
Inflammation joue un rôle primordiale
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Weksler ME et al. Immunological Reviews 205:, 244–256, 2005
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The amyloid cascade hypothesis of AD.
Blennow, K. et al. Nat. Rev. Neurol. 6, 131–144, 2010
?
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Inflammation et microglie/
macrophages périphériques
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Inflammation dans la Maladie d’Alzheimer
Glass CK. Et al. Cell 140, 918, 2010
Bon
Méchant
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Effet du vieillissement sur les cellules phagocytaire
favorisant la neuro-inflammation
des récepteurs pro-inflammatoires e.g. C5Ra
l’effet pro-inflammatoire des TLRs
de l’effet nettoyant des TLRs
des cytokines pro-inflammatoires e.g. TNF, IL-1,
IL-6, IL-8
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Cytokines
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Jimenez S et al. Neurobiol Dis 28, 11650, 2008
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Réponse immune adaptative
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Jimenez S et al. Neurobiol Dis 28, 11650, 2008
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S. Miscia et al. / Neurobiology of Aging 2007
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S. Miscia et al. / Neurobiology of Aging 2007
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Percentages of CD4+ and CD8+ cells in PBMC of AD
patients
Larbi et al. JAD 2009
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CD4+ T cell subsets in AD patients and controls
Larbi et al. JAD 2009
Ag
L
O
A
D
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In Alzheimer disease we found for adaptive immunity:
Alteration in the number of naive and memory CD4+ T cells
Alterations in membrane fluidity
Alterations in T cell proliferation
Alteration in signal transduction
Alterations in lipid rafts functions and composition
Chronic stimulation by Aβ seems to exhaust the adaptive immunity
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Et-ce que l’immunosenescence
contribue à la Maladie
d’Alzheimer?
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Relation entre immunosenescence et maladie d’Alzheimer
Le dépôt seul de A ne cause pas la maladie d’Alzheimer (intracellulaire?)
Le A n’induit pas directement la formation d’enchevêtrements neuro-fibrillaires
L’état d’activation du système immun détermine largement la neurodegeneration
L’Inflamm-aging contribue à la déposition de A par:
cytokines pro-inflammatoires
production de ROS
de signalisation intracellulaire
de cellules T trop différenciées
de cellules T naïves
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Inflamm-Aging
Naïve T cells exhaustion
Decresed CD4 activation
CD8+
Dysfunctional
Apoptosis resistant
Replicative senescent
Cytokines imbalance
TH1/TH2
Chronic inflammation
(atherosclerosis/sarcopenia
/neurodegeneration) Adaptive immune
response suppression
Chronic antigenic stimulation
CMV seropositivity
Age-related chronic inflammatory diseases
Alzheimer’s disease, atherosclerosis, cancers, frailty syndrome
General concept of immunosenescence
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Messages-clés:
Pas une, mais des « maladies d’Alzheimer »
A peut d’abord être bénéfique, mais devenir nocif sous
l’effet de l’immunosenescence (Inflamm-aging)
Inflammation est la voie commune pour toute insulte
Intervenir très tôt
Multiples cibles pour intervention
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Aging and Cancer ?
users.rcn.com/.../ D/Death_Rate_by_age.gif
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The most frequent sites for cancers in man and women
over 65 years
Men: lung Women: breast
colon lung
rectum colon
prostate rectum
bladder bladder
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Immunosurveillance\immunoediting
Zitvogel L. Nat Rev Immunol. 2006
Innate + adaptive
adaptive
+ immunosenescence
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Fulop et al.
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Pawelec and Solana, EMBO Reports 2008
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Immunosenescence & cancer:
reality or myth?
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Fulop et al.
1
3
4
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Age-related specific immune alterations favouring tumor development
1
1
3
4
4
Adapted from Whiteside TL, Oncogene 2008
CTLA-4
IL-2
IFN-γ
IL-12
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Role of age-associated cytokine dysregulation in
tumorigenesis
IL-1 production of angiogenic factors
TNF- NF-kB inducing anti-apoptosis
ROS inducing DNA damage and mutations
angiogenesis and metastasis
T cell response and Mo cytotoxicity
IL-10 T cell response and Mo cytotoxicity
TGF- T cell response (CTL) and NK cells
Treg activation
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Conclusion
Chronic antigenic stimulation by CMV, A and by cancer
antigens is additive and leads to more rapid immune
exhaustion and dysbalance in adaptive immunity, which
reduces immune capacity for responses to new antigens as
well as blunting immune responses (memory) to previously-
encountered antigens, including the chronic stressors and
create low grade inflammatory status leading to reduced
anti-cancer response with aging.
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AGING
Immune system
dysregulation
Infection
Cancer
Chronic inflammatory diseases
Autoimmune disorders
Frailty
Naïve CD4+ T cells
Immunosurveillance
Inflam-Aging
Nutrition
Loss of specificity
• Endocrine function
• Neural function
• Cardiovascular health
• Muscle homeostasis
• Glucose metabolism
• Oxidative stress
Immunosenescence
Immune Risk Phenotype
CD8+CD28-CD57+
CD4:CD8 < 1
CMV seropositivity
T-cell proliferation
+
Fulop et al. CIA, 2008
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Fragilité
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Pathophysiologic Model for Adverse
Outcomes in Older Adults
Aging
Free radicals
Senescent cells
Shortened telomeres
DNA damage
Disease
Depression
Cancer
Chronic Infection
Cardiovascular disease
Diabetes/Obesity
Frailty
Disability
Disease
Death
CRP IL-6
IGF-1 DHEA-S Cortisol
Activation of
Inflammation
Neuroendocrine
Dysregulation
Anorexia ?
Anemia
Sarcopenia
Osteoporosis
Hyperglycemia
Clotting
Triggers Physiology Outcomes
Gene Variation IL-6 DHEA-S Cortisol
Modified after Walston et coll., 2006
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Hypothesized Pathway to Frailty:
Genetic Variation
Ultimate Causes Subclinical Components
and Mechanisms
Clinically Observable
Syndrome
Distal
Outcomes
Genetics/Genetic Variation
Disease
Environment
• Decreased Function
• Loss of independence
• Increased Morbidity
• Increased Mortality
Weight loss
• Sarcopenia
• Weakness
• Exhaustion
• Slowed performance
• Low Physical
Activity
Resiliency
Robust Frail
Subclinical perturbations of
multiple physiologic systems
•Cardiovascular
Compliance
•Inflammation
•Muscle Strength
Trajectories
Walston 2006
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Aging
Diseases
Frailty
Frailty
Free radicals
Senescent cells
Shortened telomeres
DNA damage
Inflammation
Cancer
Chronic Infections
Cardiovascular disease
Diabetes/Obesity
Inflammation
Neuroendocrine Dysregulation
Metabolic alterations
Anorexia
Anemia
Sarcopenia
Osteoporosis
Hyperglycemia
Clotting
Weakness
Weight loss
Slowed
performance
Exhaustion
Low activity
Falls
Disability
Dependency
Death
Frailty 2010
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Putative alterations of major biological parameters
differentiating between aging and frailty
AGING FRAILTY
LOW GRADE INFLAMMATION HIGH GRADE INFLAMMATION
NO LIPID ALTERATIONS LIPID ALTERATIONS
IMMUNE RESPONSE: IMMUNE RESPONSE:
HORMONES: LOW HORMONES: VERY LOW
NO ANEMIA ANEMIA
NO NUTRITIONAL ALTERATIONS NUTRTITIONAL ALTERATIONS
= Aging+ syndrome
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Vaccination
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CTL B
Cellular Immunity disproportionely decreases
E
F
F
I
C
A
C
I
T
É
McElhaney 2006
Vaccination and immunosenescence
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Diminution of specific antibody production
40-70% compared to young subjects
Immune efficacy
Govaert JAMA,1994
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McElhaney 2005
Clinical effects of influenza vaccination
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EFFICACY:
•CLINICAL efficacy comparable to the general population
-Study (Christenson 2001): 259627 elderly over 65 years
-Influenza et pneumococcus
-Results: Diminution by 36% of pneumonia to pneumococcus
Diminution by 52% invasive infections by pneumococcus
Diminution of all cause mortality by 57%
•Diminution of HOSPITALISATIONS for complications
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Decrease of cell mediated immunity to
VZV related to age
Adapted with permission from AGS 2206 Dr Levin
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Vaccine against Shingles
• Randomised, double blind, placebo and
multicenter (22 centres)
– 38,546 sujets ≥60 ans
• Vaccine efficacy:
– Incidence of zona: diminution by 51.3%
– Incidence of post-herpetic neuralgia: decrease by
66.5%
– Burden of illness : decrease by 65.5%
Oxman and all. NEJM 2005
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AGAINST ALL!!
VACCINATION
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Évaluation future
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PREVENTION/
MODULATION?
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INTERVENTIONS POTENTIELLES
1. Vaccination contre maladies infectieuses et infections virales chroniques
2. Rajeunissement du Thymus
3. Stratégies anti-cytokines pro-inflammatoires : Ac Anti-cytokine
pro-inflammatoires
Neutralisations des récepteurs
4. Restauration de la susceptibilité des cellules CD8+ T à l’apoptose
5. Restauration de la longueur du telomere: Telomerase
Telomere binding protein
6. Re-expression du CD28 co-récepteur à la surface des cellules T
7. Thérapie de cellules souche
8. Modulation des cellules T régulatrices (CD4+CD25+)
9. Nutrition: Macro-nutriments
Micro-nutriments
10.Hormones: Oestrogen
Dehydroepiandrosterone
Insulin growth factor I
11. Manipulations génétiques
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Inflamm-Aging
Naïve T cells exhaustion
Decresed CD4 activation
CD8+
Dysfunctional
Apoptosis resistant
Replicative senescent
Cytokines imbalance
TH1/TH2
Chronic inflammation
(atherosclerosis/sarcopenia
/neurodegeneration) Adaptive immune
response suppression
Chronic antigenic stimulation
CMV seropositivity
Age-related chronic inflammatory diseases
Alzheimer’s disease, atherosclerosis, cancers, frailty syndrome
General concept of immunosenescence
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GENERAL CONCLUSIONS
WITH AGING IT EXISTS ALTERATIONS IN THE IMMUNE RESPONSE:
IMMUNOSENESCENCE: ESPECIALLY IN THE CELLULAR IMMUNE
RESPONSE, MAINLY CD4 T CELLS
ONE OF THE FUNDAMENTAL ALTERATIONS COULD BE THE
AUGMENTATION OF CHOLESTEROL RENDERING THE
MEMBRANE MORE RIGID
THESE CHANGES EXPLAIN THE INFAMM-AGING LEADING
TO AUGMENTATION OF INFECTIONS, CANCERS, AUTOIMMUNE
DISORDERS, ALZHEIMER’S DISEASE AND LOW-GRADE
INFLAMMATION
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The Tower of Babel by Pieter Brueghel the elder (1525-69).
He conceived it as an allegory of pride and human frailty.
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Acknowledgements
Prof Gilles DUPUIS
Prof Abdelouahed KHALIL
Dre Nadine DOUZIECH
Dre Krassimira Tsvetkova Mme Nancy Allard Dr Hugo Garneau Mme Annie Larouche
Dr Carl Fortin Prof Eric Frost Prof Graham Pawelec MERCI !
FUNDS:
IRSC
CRSNG
CDA
RQRV
Dr. Anis Larbi